HIV-associated neurocognitive disorder is clinically defined by a combination of motor, cognitive, and behavioral deficits that result from progressive neuronal damage. Although a constellation of factors contributes to the neurodegeneration that occurs in HAND, the precise mechanism leading to neuronal damage remains unelucidated. Interestingly, the cell cycle machinery, specifically E2F1, has been implicated in many neurodegenerative diseases including HAND. However, both the physiologic and the pathologic roles of this cell cycle-related protein remain poorly understood. Ultimately, this new knowledge will lead to a novel therapeutic strategy of targeting the preservation of E2F1 physiologic function while simultaneously blocking its pathologic activity for treating HAND and other neurodegenerative diseases. The preliminary data provided in this proposal suggests that E2F1 binds RNA and plays a role in synaptic specialization, thus leading to the specific hypothesis of which E2F1 regulates synaptic specialization through its RNA binding activity in postmitotic neurons. To determine the role of E2F1 in synaptic specialization, E2F1 will be depleted using RNA interference technology or genetic knockout animals and assay for changes in dendritic arborization, spine morphogenesis, PSD95 clustering, and synapse number. To determine the role of E2F1 RNA binding activity in neurons, the RNA binding activity will be inhibited with dominant negative constructs lacking RNA binding domain or containing RNA competitive ligand and assay for changes in neuronal viability, stability of target ligands, and synaptic specializations. The results from these experiments will identify the physiologic role of E2F1 in postmitotic neurons and its potential pathologic contributions in HAND. PUBLIC HEALTH RELEVANCE: Patients with HIV-associated dementia exhibit increased expression of cell cycle-related protein E2F1. However, little is known about its physiologic role in neurons and its pathologic role in neurodegeneration. We believe that identifying its physiologic function in neurons will lead to novel therapeutic strategy of targeting E2F1 to prevent neuronal damage and subsequent cognitive decline in HIV-associated dementia.